Chiang Jing Wang, Karlan Beth Y, Cass Llana, Baldwin Rae Lynn
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard., 160W, Los Angeles, CA 90048, USA.
Gynecol Oncol. 2006 Jun;101(3):403-10. doi: 10.1016/j.ygyno.2005.10.034. Epub 2005 Dec 19.
To compare the clinical outcome of ovarian cancer patients whose tumors contain BRCA1 genes silenced by promoter hypermethylation to patients with germline BRCA1 mutations and to patients with wild-type BRCA genes.
Ovarian cancers from a hospital-based tumor bank were characterized as having a BRCA1 mutation; or a methylated BRCA1, BRCA1 pseudogene or MLH1 promotor; or a wild-type BRCA gene. Survival of patients with methylated BRCA1 promoters (N = 11) was compared to that of patients with wild-type BRCA genes (N = 30) and BRCA1 mutations (N = 22). A methylator phenotype was defined to include tumors with hypermethylation of BRCA1, hMLH1 and/or dBRCA1 pseudogene promoters (N = 23).
All cohorts had comparable clinical factors except for age at diagnosis. Median age of methylated BRCA1 and wild-type BRCA patients was older than BRCA1 mutation carriers (60 and 63 versus 48 years; P = 0.04). The median disease-free interval was significantly shorter for patients with a methylated BRCA1 promoter (9.8 months) than for BRCA1 mutation carriers (39.5 months; P = 0.04). Median overall survival was also significantly shorter for patients with a methylated BRCA1 promoter (35.6 months) than BRCA1 mutation carriers (78.6 months; P = 0.02). The combined methylator phenotype cohort had significantly shorter survival (36.1 months) compared to wild-type BRCA patients (63.3 months; P = 0.02).
These data suggest that methylation of the BRCA1 promoter is associated with poor patient outcome. BRCA1 may be part of a global panel of methylated genes associated with aggressive disease.
比较肿瘤中BRCA1基因因启动子高甲基化而沉默的卵巢癌患者与携带种系BRCA1突变的患者以及野生型BRCA基因患者的临床结局。
对一家医院肿瘤库中的卵巢癌进行特征分析，确定其具有BRCA1突变；或BRCA1、BRCA1假基因或MLH1启动子甲基化；或野生型BRCA基因。将BRCA1启动子甲基化患者（N = 11）的生存率与野生型BRCA基因患者（N = 30）和BRCA1突变患者（N = 22）的生存率进行比较。甲基化表型定义为包括BRCA1、hMLH1和/或dBRCA1假基因启动子高甲基化的肿瘤（N = 23）。
除诊断年龄外，所有队列的临床因素具有可比性。BRCA1甲基化患者和野生型BRCA患者的中位年龄高于BRCA1突变携带者（分别为60岁和63岁，而BRCA1突变携带者为4岁；P = 0.04）。BRCA1启动子甲基化患者的无病生存期（9.8个月）明显短于BRCA1突变携带者（39.5个月；P = 0.04）。BRCA1启动子甲基化患者的总生存期（35.6个月）也明显短于BRCA1突变携带者（78.6个月；P = 0.02）。与野生型BRCA患者（63.3个月；P = 0.02）相比，联合甲基化表型队列的生存期明显较短（36.1个月）。
这些数据表明BRCA1启动子甲基化与患者预后不良有关。BRCA1可能是与侵袭性疾病相关甲基化基因的整体组成部分。
